Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:12][I:13]>C(O)C>[I-:13].[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[CH:7][N+:8]([CH3:12])=[CH:9][CH:10]=1)=[O:11])[CH3:2]
Reactant: CCOC(=O)c1ccncc1
Reactant: CI
Solvent: CCO
Product: CCOC(=O)c1cc[n+](C)cc1
Product: [I-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Isonicotinic acid ethyl ester (5 g, 33 mmol), was dissolved in ethanol (40 mL). Methyl iodide (4.13 mL, 66.1 mmol) was added and the clear solution was stirred overnight at 60° C. The resulting mixture was evaporated to yield a red/orange solid, which was determined by 1H NMR and thin-layer chromatography (TLC) to be the title product in quantitative yield. The crude mixture was used directly in the following reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13].CN(C)C=O>O>[F:10][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[C:5]=1[OH:9])[C:12]#[N:13]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 4-bromo-2,6-difluorophenol (4.00 g, 19.0 mmol), copper (I) cyanide (1.72 g, 19.0 mmol), and dimethylformamide (40 mL) was refluxed for 6 hours, cooled to room temperature, diluted with water (150 mL), and filtered. The tan solids obtained were washed with water and retained. The combined filtrates were acidified (1N HCl) and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (Silica Gel 60, 20% ethyl acetate in hexanes) to give 1.03 g of pure title compound as an off-white solid, mp 195°-197° C.
Reaction SMILES: [OH-].[NH4+].[C:3]([NH:10][C:11]1[C:20]([N+:21]([O-:23])=O)=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16]2)([C:5](OCC)=[O:6])=[O:4]>O.CN(C)C=O.O1CCCC1.[Pt]>[OH:23][N:21]1[C:20]2[CH:19]=[CH:18][C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11]=2[NH:10][C:3](=[O:4])[C:5]1=[O:6]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])ccc2c1CCCC2
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2c3c(ccc2n(O)c1=O)CCCC3
Yield: 47.4 %

Procedure:
A solution of 25% ammonium hydroxide in water (0.7 ml) was added to a solution of 5-ethoxalylamino-1,2,3,4-tetrahydro6-nitronaphthalene (0.30 g, 1 mmol) in a mixture of 10 ml of N,N-dimethylformamide and 30 ml of tetrahydrofuran. The mixture was hydrogenated at atmospheric pressure and room temperature in the presence of 5% platinum on carbon, until the starting material had disappeared. The mixture was filtered and the filtrate was discarded. Now the filter was washed with 5% aqueous potassium hydroxide, and the filtrate was acidified with 4N hydrochloric acid. The white precipitate was isolated by filtration and washed with water and ethanol to give 0.11 g (46%) of the title compound. M.p. >225° C. dec.; 1H-NMR (DMSO-d6): 1.57-1.90 (m, 4H, 2CH2), 2.50-2.93 (m, 4H, 2CH2), 6.95 (d, J =9 Hz, 1H, ArH), 7.30 (d, J =9 Hz, 1H, ArH); appr. 11.1 (very broad s, 1H, NH); IR (KBr): 1670 cm-1; MS (m/e): 232 (..M+, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11](O)=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH2:14]([O:16][C:17](=[O:31])[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:19][NH2:20])[CH3:15].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(OCC)(=O)C>[CH2:14]([O:16][C:17](=[O:31])[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH2:19][NH:20][C:11](=[O:12])[CH2:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:15]
Reactant: CCOC(=O)C(CN)c1ccc(OC)c(OC)c1
Reactant: COc1cc(C)cc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CNC(=O)Cc1cc(C)cc(OC)c1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
A solution of (3-methoxy-5-methyl-phenyl)-acetic acid (512.8 mg, 2.84 mmol), 3-amino-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester (825 mg, 2.84 mmol), and triethylamine (912 uL, 6.54 mmol) in dry methylene chloride (25 mL) was chilled in an ice bath under argon. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (573 mg, 2.98 mmol) was added in one portion and the mixture stirred at room temperature for 72 hrs. The reaction mixture was poured into ethyl acetate (100 mL) and extracted with 2.5% aqueous potassium bisulfate (3×20 mL), 5% aqueous sodium bicarbonate (3×20 mL), and saturated aqueous sodium chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford 2-(3,4-dimethoxy-phenyl)-3-[2-(3-methoxy-5-methyl-phenyl)-acetylamino]-propionic acid ethyl ester as a light tan foam (0.79 g, 67%). This material was used without further purification: 1H NMR (300 MHz) compatible.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23](Cl)[CH:22]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:20]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[N:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([C:52]3[CH:53]=[CH:54][N:49]=[CH:50][CH:51]=3)[N:24]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC(COc1cccc(-c2nc(Cl)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(COc1cccc(-c2nc(-c3ccncc3)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (160 mg, 0.26 mmol) in degassed dioxane and H2O (4/1, 25 mL) was added Na2CO3 (83 mg, 0.78 mmol); Pd(PPh3)4 (30 mg, 0.026 mmol) and pyridin-4-ylboronic acid (64 mg, 0.52 mmol). The system was purged with N2 stream and the mixture was stirred 100° C. for 2 h., cooled down to room temperature, diluted with water (25 mL) and extracted with EtOAc (25 mL×2). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc=10/1 to 1/1) to give [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (128 mg, 75% yield). ESI-LCMS (m/z): 664.4 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[C@@H:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.C(OC(=O)[NH:75][CH2:76][CH2:77][C:78]1[CH:83]=[CH:82][C:81](O)=[CH:80][CH:79]=1)(C)(C)C.Cl>O1CCCC1>[NH3:21].[NH2:75][CH2:76][CH2:77][C:78]1[CH:83]=[CH:82][C:81]([O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([C@@H:18]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:19][CH2:20][N:21]([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:23])[CH3:24])[CH:11]=2)=[CH:80][CH:79]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCO)ccc1OCc1ccccc1)C(C)C
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2ccc(CCN)cc2)ccc1OCc1ccccc1)C(C)C
Product: N
Reaction time: 0.33 h

Procedure:
2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethanol (Prepared according to WO9843942, 390 mg, 0.88 mmol) was dissolved in tetrahydrofuran (6 ml), triphenylphosphine (344 mg, 1.31 mmol) then di-tert-butyl(E)-diazene-1,2-dicarboxylate (265 mg, 1.31 mmol) was added and the mixture was stirred for 20 minutes. tert-butyl[2-(4-hydroxyphenyl)ethyl]carbamate (Prepared according to WO2004/020415, 311 mg, 1.31 mmol) was then added and the reaction was stirred over night. Hydrogen chloride (4M in diethyl ether, ml) was added and left to stir for 3 days, then hydrochloric acid (2M, 5 ml) was added and after 1 hour the mixture was washed with diethyl ether, basified with 2N sodium hydroxide, extracte with diethyl ether, dried (magnesium sulphate), filtered and the solvents removed in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (242/8/0.8 to 95/5/0.5 by volume) to furnish the title compound as a colourless oil, 100 mg.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)=O>CN(C)C=O.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1
Reactant: FC(F)(F)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CSc1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A two-necked flask having a dry ice condenser fitted on top was charged with 50 ml of dry dimethylformamide and 2 g of a 60% strength by weight suspension of sodium hydride in paraffin, and subsequently 7.3 g of 4-chlorothiophenol in 10 ml of dimethylformamide were added dropwise. Chlorotrifluoroethane was then passed in at a reaction temperature of about 60° C., until the gas began to condense in the dry ice condenser. The mixture was stirred for a further 5 hours and the course of the reaction was monitored by thin-layer chromatography (silica gel; ethyl acetate/petroleum ether 1/5). The reaction mixture was worked up by pouring into water and extracting with dichloromethane. The combined organic extracts were dried and the solvent was distilled off at reduced pressure. The oily residue was subsequently distilled (43°-45° C./0.1 mbar), giving 8.8 g of 4-chloro(2',2',2'-trifluoroethylthio)benzene
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:17]([C:18](=[O:20])[CH3:19])=[C:16]([CH3:21])[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:14](=[O:32])[N:13]1[CH3:33].[OH-].[Li+].O.Cl>O1CCOCC1>[C:18]([C:17]1[CH:12]([C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[C:3]([OH:34])=[O:2])[N:13]([CH3:33])[C:14](=[O:32])[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:16]=1[CH3:21])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C#N)ccc1C1C(C(C)=O)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid methyl ester (intermediate 5)(612 mg, 1.30 mmol) and lithium hydroxide (93.3 mg, 3.90 mmol) are stirred in 1,4-dioxane (12.0 ml) and water (6.0 mL) at room temperature for 20 min Water (200 mL) is added and the mixture is acidified with hydrochloric acid (1.0 M, 44 mL) to a pH value of 3. The aqueous phase is extracted with ethyl acetate. The organic phase is washed twice with water, dried over MgSO4 and concentrated. Yield: 665 mg. ESI mass spectrum: [M+H]+=472; Retention time HPLC: 1.09 min (HPLC method Z018_S04).
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].B(F)(F)F.[CH3:12][CH2:13][O:14][CH2:15][CH3:16].[O:17]1C=CC[CH2:18]1.[OH-].[Na+]>CO>[CH3:7][O:6][CH:3]([O:4][CH3:5])[CH:12]1[CH2:16][CH2:15][O:14][CH:13]1[O:17][CH3:18]
Reactant: C1=COCC1
Reactant: CCOCC
Reactant: COC(OC)OC
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(OC)C1CCOC1OC
Reaction time: 16 h

Procedure:
Into a dried 3L three neck-round bottom flask with a stirrer bar, nitrogen-inlet, thermocouple and a 1L-addition funnel was charged 1227.2 g (11.56 mol) of trimethyl-orthoformate, which was cooled to −5° C. to −3° C. while agitating. The reaction mixture was charged with 3.855 g BF3.Et2O (21 mmol) while agitating under nitrogen. The addition funnel was then charged with a mixture of 315.41 g 2,3-dihydrofurane (4.5 mol) and 434.64 g trimethylorthoformate (4.1 mol) and this mixture was added to the reaction mixture over a period of 160-180 minutes while maintaining the temperature at −5° to −3° C. After the addition was complete, the reaction was quenched with 3.24 g NaOH (81 mmol) in 12.96 g MeOH and left 16 h at 15° C. The reaction mixture was filtered and distilled first under atmospheric pressure, then under reduced pressure. The intermediate product obtained boils at 79-85° C. at 6.8-6.9 mmHg and is a mixture of diastereomers.
Reaction SMILES: [Na].[OH:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]=1[C:26](=[O:28])[CH3:27].[OH-].[Na+].[Br:31][CH2:32][CH2:33][CH2:34]Br>C1COCC1>[C:26]([C:4]1[CH:5]=[CH:6][C:7]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]3[N:22]=[N:23][N:24]([CH2:34][CH2:33][CH2:32][Br:31])[N:25]=3)=[CH:16][CH:15]=2)=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]=1[OH:2])(=[O:28])[CH3:27]
Reactant: CCCc1c(COc2ccc(Cc3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Reactant: BrCCCBr
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(COc2ccc(Cc3nnn(CCCBr)n3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.8 %

Procedure:
1-[2-Hydroxy-3-propyl-4-((4-(1H-tetrazol-5-ylmethyl)phenoxy)methyl)phenyl]ethanone sodium salt (15 g, 0.039 mol) was added to THF (150 ml) and the minimum amount of lN sodium hydroxide soluton was added to effect solution. 1,3-Dibromopropane (12.12 g, 0.06 mol) was added and the reaction solution was stirred at room temperature for 24 hours. The reaction mixuture was concentrated in vacuo. Water was added to the concentrate and the resultant mixture was extracted with ethyl acetate (3×). The organic layers were combined, washed with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue was chromatographed by HPLC on a silica gel column eluted with a mixture of 9:1 toluene:ethyl acetate to yield 3.0 g of a light yellow oil of the 2H-tetrazole-2-isomer of the above product.
Reaction SMILES: [CH3:1][C:2]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:4]2[C:5](OC(=O)[NH:9][C:3]=12)=[O:6].O.[NH3:16]>CN(C=O)C.O>[NH2:9][C:3]1[C:2]([CH3:1])=[C:13]([Cl:14])[CH:12]=[CH:11][C:4]=1[C:5]([NH2:16])=[O:6]
Reactant: Cc1c(Cl)ccc2c(=O)oc(=O)[nH]c12
Reactant: N
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)ccc(C(N)=O)c1N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Using two inlets, at 80° C. a suspension of 4.64 g (0.0219 mol) of 3-methyl-4-chloroisatoic anhydride in 21 ml of DMF and 3.1 g (0.0219 mol) of 25% strength ammonia water in 6 ml of water were added simultaneously with stirring and over a period of 15 min to 8 ml of water. The mixture was stirred at 80° C. for 1 h and then cooled and extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, giving 2.61 g (64.4% of theory) of the title compound as colorless crystals of m.p. 206-208° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([NH:9][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:11][OH:12])=[N:6][C:7]=1[CH3:8].[C:29](O)(=O)C.C(N)=N>CCO>[CH:26]1([C:24]2[NH:23][N:22]=[C:21]([N:20]3[CH:29]=[N:1][C:2]4[C:3]3=[N:4][C:5]([NH:9][C@H:10]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][OH:12])=[N:6][C:7]=4[CH3:8])[CH:25]=2)[CH2:28][CH2:27]1
Reactant: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc(Nc2cc(C3CC3)[nH]n2)c1N
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Product: Cc1nc(N[C@@H](CO)c2ccc(F)cc2)nc2c1ncn2-c1cc(C2CC2)[nH]n1
Yield: 35 %

Procedure:
A mixture of (R)-2-[5-amino-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-methylpyrimidin-2-ylamino]-2-(4-fluorophenyl)ethanol (Method 40; 0.3 g, 0.8 mmol) and formamidine acetate (0.2 g, 1.6 mmol) in EtOH (8 ml) was heated to reflux for 12 hours. The reaction was then concentrated, dissolved in DCM (50 ml), and washed with saturated NaHCO3 solution (50 ml). The organic layer was then dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM:MeOH=20:1) to give the title compound (0.11 g, 35%). NMR (400 MHz, CD3OD) 8.32 (s, 1H), 7.46-7.43 (m, 2H), 7.06-7.02 (m, 2H), 6.24 (s, 1H), 5.10-5.02 (m, 1H), 3.87-3.75 (m, 2H), 2.61 (s, 3H), 1.99-1.96 (m, 1H), 1.10-1.08 (m, 2H), 0.80-0.75 (m, 2H). MS: Calcd.: 393; Found: [M+H]+ 394.
Reaction SMILES: [C:1]([O:4][CH:5]1[O:22][C@@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].OCC[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.B(F)(F)F.CCOCC.CCN(CC)CC>C(C#N)(C)=O>[C:8]([O:7][C@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:21]([CH3:23])[O:22][C@H:5]1[O:4][CH2:1][CH2:2][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(NCCO)OCc1ccccc1
Agent: CC(=O)C#N
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@H](OCCNC(=O)OCc2ccccc2)O[C@@H](C)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1,2,3,4-tetra-O-acetyl-L-fucopyranose (200 g, 601.86 mmol) in AcCN (100 mL) and benzyl (2-hydroxyethyl)carbamate (140.96 g, 722.08 mmol) at 0° C. was added BF3.Et2O (427.7 g, 3.01 mol) dropwise over 2 hr. After stirring at rt for 16 hr, the reaction mixture was cooled to 0° C. and followed by the addition of Et3N (130 mL). The resulting mixture was concentrated and the residual was dissolved in CH2Cl2 (2.0 L), which was subsequently washed with sat. NaHCO3 (2×500 mL), water (2×500 mL) and brine (500 mL). The organic phase was separated, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with EtOAc/petroleum ether (1:3) to give the title compound. 1H NMR (CDCl3) δ 7.33-7.37(5H, m), 5.12-5.32(5H, m), 4.99-5.04(1H, m), 4.42-4.45 (1H, d), 3.87-3.94 (1H, m), 3.78-3.84 (1H, m), 3.66-3.70(1H, m), 3.42-3.44 (2H, m), 2.19 (3H, s), 2.05-2.12(6H, m), 1.25-1.30 (3H, d).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:4]2[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[CH2:3]2)=[N:9][CH:10]=1)#[N:13]
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(N2CCCC(N)C2)nc1
Product: N#Cc1ccc(N2CCCC(NC(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)C2)nc1
Yield: 44 %

Procedure:
This compound was synthesized from 6-(3-aminopiperidin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (75 mg, yield 44%). 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=2.1 Hz, 1H), 8.36 (s, 1H), 8.27 (d, J=7.6 Hz, 1H), 8.00-7.98 (dd, J=7.8 Hz, 1.1 Hz, 1H), 7.65-7.61 (m, 2H), 6.77 (d, J=9.2 Hz, 1H), 6.63 (d, J=6.1 Hz, 1H), 4.24-4.21 (dt, J=6.7 Hz, 3.4 Hz, 1H), 4.00-3.98 (m, 1H), 3.91-3.80 (m, 2H), 3.64-3.58 (m, 1H), 2.12-2.05 (ddd, J=13.0 Hz, 8.6 Hz, 4.3 Hz, 1H), 2.03-1.96 (m, 1H), 1.89-1.82 (m, 1H), 1.77-1.69 (m, 1H). MS (ESI) m/z: Calculated for C21H17F3N6O2: 486.13. found: 487.2 (M+H)+
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:28]([O:30][CH3:31])=[O:29])[CH2:9][NH:10][C:11]([O:13][CH2:14][CH:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])=O)C>FC(F)(F)C(O)=O.ClCCl>[CH:17]1[C:16]2[CH:15]([CH2:14][O:13][C:11]([NH:10][CH2:9][C@@H:8]([C:28]([O:30][CH3:31])=[O:29])[NH2:7])=[O:12])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CNC(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester (Example 62; 200 mg, 0.45 mmol) in trifluoroacetic acid/dichloromethane (1:1; 2 mL) was stirred at room temperature for 40 min. The solvent was evaporated and ethyl acetate (10 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SO4), filtered and evaporated to give 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-L-alanine, methyl ester. HOAT (73 mg, 0.45 mmol), DCC (111 mg, 0.45 mmol), 2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]-benzoic acid (Example 36; 148 mg, 0.45 mmol) and N,N-dimethylformamide (5 mL) were added and the solution was stirred at room temperature for 1.5 h. Water was added and the solution was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, evaporated, and chromatographed (40–80% ethyl acetate/hexanes) to give 3-[(9H-fluoren-9-ylmethoxy)carbonyl]amino-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine, methyl ester (116 mg, 40%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCOCC>CN(C=O)C>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: COc1ccc(N)cc1
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(NCCn2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
2-(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (1.00 g, 2.7 mM, prepared in Example 4a. and p-anisidine (1.33 g, 10.8 mM) were stirred and heated to reflux in DMF (20 mL) for 1.5 hours to give a brown solution. The solution was cooled to room temperature and ether (80 mL) was added to give a dark suspension. The suspension was stirred for two hours and filtered. The collected solids were washed with ether (150 mL) to give the title compound as a tan powder (1.17 g, 60%), mp 239-241° C.; MS(CI):413.